Optical Sensor Element for Analyte Assay in a Biological Fluid, and Method of Manufacture Thereof

ABSTRACT

Beginning with a sheet of optically transparent material, one may fabricate a great many shaped optical wafers, each in the form of a thin and essentially flat piece of optical material having a narrow cross-sectional width relative to length, and a sharply narrowed tip at one end. The fabrication process involves passing a sheet of optically transparent material through one or more operational steps wherein cutting, shearing, embossing, microperforating, or a combination thereof is performed. The fabrication process may further include a cladding operation, a tip texturing operation, and an analyte-reactive reagent deposition operation. The completed optical wafers are separated and each may be mounted into a user-operated device along with systems for educing a fluid sample to be expressed from a living organism, for bringing the tip of the optical wafer into contact with the fluid sample, and for illuminating and assaying the fluid sample.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to sensing analyte concentration in abiological fluid, and more particularly to an optical sensor element formeasuring analyte concentration in a biological fluid by optical meansand a method of manufacture thereof.

2. Description of Related Art

Optical sensors using waveguides such as optical fibers are very usefulin performing analyte assays in biological fluids. U.S. Pat. No.5,859,937 issued Jan. 12, 1999 to Nomura, for example, describes aminimally invasive medical testing device and method for its use whichutilizes a light-conducting optical fiber sensor element having alocalized textured site thereon, wherein a reagent is deposited.Interaction of the reagent with an analyte specific to the reagentproduces a response, such as development of a colored product, which isdetectable by means of a change in characteristics of a light beamtransmittable through the optical fiber. By means of the textured siteand its increased surface area, the sensitivity of the medical testingdevice is greatly enhanced. The sensor is particularly useful in bloodglucose determinations, requiring smaller blood samples than flat stripdevices. Improvements in such optical fiber sensor elements have evenfurther increased their sensitivity. Examples of such improved opticalfiber sensor elements may be found in, for example, United StatesPublished Patent Application No. 2009/0219509 published Sep. 3, 2009 inthe name of Nomura, United States Published Patent Application No.2011/0097755 published Apr. 28, 2011 in the name of Nomura, and U.S.Pat. No. 8,008,068 issued Aug. 30, 2011 to Nomura.

The handling of individual optic fibers during manufacture is notwithout difficulty in a practical industrial process. Steps wouldnormally include cutting optic fibers into short lengths, attaching themto some form of belt or carrier, exposing a belted bundle or continuousarray of optic fiber ends to an etchant such as a stream of atomicoxygen gas, then depositing a mixture of analyte-reactive reagent andhollow polymeric particles on the treated tips, followed by drying andrepositioning of such treated fibers into cartridges for use by aconsumer such as a diabetic patient. Improvements in optical sensorelements to enhance their manufacturability and improvements in themethods of manufacture thereof are desirable.

BRIEF SUMMARY OF THE INVENTION

One embodiment of the present invention is an optical sensor element fordetermination of an analyte in a biological fluid, comprising a flatoptical waveguide elongated in a longitudinal direction and having twoparallel major surfaces and an edge contiguous to the major surfaces, aportion of the edge being a tip transverse to the longitudinaldirection, a further portion of the edge being a base transverse to thelongitudinal direction, and further portions of the edge being two sidesextending between the base and the tip generally in the longitudinaldirection. The tip is textured, the major surfaces are coated withcladding; and each of the sides is partially coated with cladding towardthe base and being fully coated with cladding toward the tip. Theoptical sensor element further comprises an analyte-reactive reagentdisposed on the tip.

Another embodiment of the preset invention is an optical wafer for usein manufacturing an optical sensor element, comprising a flat opticallytransparent body elongated in a longitudinal direction and tapering downat one end to a tip, the tip being transverse to the longitudinaldirection and presenting a textured field of elongated projections; andan analyte-reactive reagent disposed on the tip.

Another embodiment of the preset invention is a method of fabricatingoptical wafers for biological fluid sensors, comprising: establishing aplurality of cutouts in a sheet of optically transparent polymermaterial to define respective tapered portions of the optical wafers andexpose edges thereof; establishing a plurality of transverse lines inthe sheet to define respective main portions of the optical wafers andpartially expose edges thereof; separating the sheet along a pluralityof longitudinal lines into a plurality of strips to expose respectivetips of the optical wafers; applying a texturing treatment to the tipsexposed in the separating step to form a field of elongated projectionsin the tips; depositing a fluid slurry mixture of analyte-reactivereagent and light scattering particles within the field of elongatedprojections; and following the texturing treatment applying step and thefluid slurry mixture depositing step, separating the optical wafers fromone another along the transverse lines.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 is a pattern drawing of a sheet of optical material having linesof separation therein for defining optical wafers.

FIG. 2 is a perspective drawing showing a partial separation of sectionsof the optical material of FIG. 1 into strips of optical wafers.

FIG. 3 is a 3-dimensional drawing of a strip of optical wafers of FIG. 2as rolled into a roll of optical wafers connected along their sides andhaving projecting tips.

FIG. 4 is a 3-dimensional drawing of an individual optical wafer of thetype shown in FIGS. 1, 2 and 3.

FIG. 5 is a flowchart of a method of manufacture of optical wafers.

FIG. 6 is a schematic drawing of various cutouts suitable for formingthe optical wafers.

DETAILED DESCRIPTION OF THE INVENTION

Various optical fiber sensor elements are described in U.S. Pat. No.5,859,937 issued Jan. 12, 1999 to Nomura, United States Published PatentApplication No. 2009/0219509 published Sep. 3, 2009 in the name ofNomura, United States Published Patent Application No. 2011/0097755published Apr. 28, 2011 in the name of Nomura, and U.S. Pat. No.8,008,068 issued Aug. 30, 2011 to Nomura, all of which are incorporatedherein in their entirety by reference thereto, and collectively referredto herein as the Nomura patent documents. Some of the optical sensorelements described herein possess many of the analytical advantages ofthese earlier optical fiber sensor elements, including a one-steptesting process for analyte measurement, analyses of analytes in verysmall sample volumes in contact with a very small tip (a blood samplesize of only around 0.1 microliter in diabetes blood glucose testing,for example), rapid test results of two seconds or less, and eliminationof hemoglobin interference. However, in addition, such optical sensorelements are also suitable for manufacture by highly efficient andcost-effective methods which avoid some of the manufacturing andhandling disadvantages that arise in the manipulation of short lengthsof optical fibers, and substantially reduce manufacturing costs.

At least one of the implementations described herein may start with asheet of optically transparent material, and derives therefrom a shapedoptical wafer in the form of a thin and preferably flat piece of opticalmaterial having a narrow cross-sectional width relative to length, andfurther having a sharply narrowed tip at one end of the length of theshaped body, this tip approximating the same cross-sectional distal areaas the distal tip of a comparable optic fiber as described in thepreviously-referenced Nomura patent documents. To form the opticalwafers, the sheet of optically transparent material is passed throughone or more operational steps wherein cutting (including scoring),shearing, embossing, micro-perforating, or any combination of cutting/shearing/ embossing/ micro-perforating/ of the material is performed.Where scoring or embossing is used, to form lines, the lines may beformed on only one side of the sheet, or may be formed on both sides inregistration with one another. The purpose of these operational steps isto prepare an elongated optical body, which may be referred to as anoptical wafer, having in general the optical sensing characteristics ofan optical fiber sensor but being of a different shape than a fiber soas to facilitate manufacture and post-manufacture handling. At least oneof the implementations may further include sufficient cladding of theelongated optical body, texturing of a distal tip of the elongatedoptical body, and the modification of the textured tip with ananalyte-reactive reagent composition that provides, for instance, acolorimetric change when contacted with a fluid containing theassociative analyte. At least one of the implementations may furtherinclude a user-operated device containing the elongated optical body,any suitable mechanism for bringing the tip of the elongated opticalbody into contact with a fluid sample to be tested, and any suitableoptical system for coupling light to and from the optical body (such asa lens, grating coupler, or prism coupler) via its base in order toilluminate the tip and to assay light reflectance received by the tipfor correlative assay of an analyte. At least one of the implementationsmay further include any suitable mechanism for educing a fluid sample tobe expressed from a living organism, such as by a lancet.

FIGS. 1 through 4 show the results of various steps of an illustrativemanufacturing process shown in the flowchart of FIG. 5.

FIG. 1 shows an exemplary implementation of a suitable pattern that maybe formed in a sheet or in continuous sheeting of optically transparentmaterial that lead to individual optical wafers when complete. Shown inFIG. 1 is a sheet or a section of a continuous sheeting that containsembossed or cut longitudinal lines 10 and 11 in the machine direction,embossed or cut transverse lines 12 in the transverse direction, andoval embossed or cut cutout lines 13. These lines may be formed at thesame time as shown in block 51 of the illustrative manufacturing process50 shown in FIG. 5, or may be formed at different times. Illustratively,the cutout lines 13 and the transverse lines 12 may be formed togetherfirst, and the longitudinal lines 10 and 11 may be formed later in themanufacturing process. Alternatively, the cutout lines 13 may be formedand the cutouts 15 removed (for example, punched out) before thetransverse lines 12 are formed. If the cutouts are both defined andremoved using punches having shaped cutting edges, the cutout lines 13are not needed. Guide holes 16 may be provided to assist in operationsrequiring high precision, such as punching, embossing, and cutting.

The cutouts 15 provide for the narrowing of a portion of the outlinedoptical wafers 14. Other shapes such as circular, diamond, rectangle,triangular, and so forth may alternatively be used for the cutouts 15,and the selection of a specific shape may be influenced by such designconsiderations as the optical performance of the light guide which isformed from the optical wafer, and handling considerations duringmanufacture. From a manufacturing perspective, circular and oval shapedcutouts 15 may be preferable to avoid stress regions during manufacture,in that no sharp corners or recesses are present that would interferewith punching out of the cutouts 15. All embossed or cut lines need notbe formed in a single process step. In one implementation, for example,separation of portions of the sheet material involves sequentialoperations. Note that the orientation of transverse versusmachine-direction lines may be varied or transposed, particularly if thestarting material consists of single sheets of optical material.However, when starting with continuous sheeting as with a long roll ofoptical material sheeting, the arrangement of lines and theirorientation as illustrated in FIG. 1 is particularly advantageous.

As shown in blocks 51 and 52 of FIG. 5, transverse lines 12 andoptionally cutout lines 13 and longitudinal lines 10 and 11 may beformed in the sheet of optical material (block 51), and the cutouts 15may be removed from the sheet of optical material by punching them out.The organization of blocks 51 and 52 is not to be understood to requirea particular order, and the process steps may be performed in variousways and in a different order. In one illustrative implementation, allembossed or cut lines including the cutout lines 13 may be formedtogether, and the cutouts 15 subsequently punched out. In anotherillustrative implementation, the cutouts may be punched out using asuitable cutting punch without forming any cutout lines 13, followed byformation of the transverse lines 12, and followed later in themanufacturing process by formation of the longitudinal lines 10 and 11.Any suitable technique such as embossing, microperforating, or partialcutting of the optical material may be used to form the longitudinallines 10 and 11, the transverse lines 12, and the cutout lines 13.

Light guides use cladding on their optical material to confine the lightand to minimize loss of light through the outer walls. Although claddingof the optical sheeting may be employed before or after the embossing orcutting steps, it is advantageous to perform the cladding operationafter the cutouts 15 are removed and the transverse lines 12 are formedin the sheet of optical material, so that the tapered sidewalls of theoptical wafer flanking the tip are cladded, and so that the mainsidewalls of the optical wafer as defined by the transverse lines 12 areat least partially cladded, to improve optical performance. While thelongitudinal lines 10 and 11 may be formed prior to the claddingoperation, some implementations may benefit from forming either or bothof the longitudinal lines 10 and 11 after the cladding operation, sothat the tips, bases or both of the separated optical wafers are free ofany cladding. Cladding may be performed by dip-coating, spraying,roller-coating, or similar such methods. A particularly suitablecladding technique is deposit of a cladding material by plasmapolymerization. Plasma polymerization provides for pinhole-free coatingsand also achieves penetration into embossed or microperforated recesses.Effective cladding compounds typically have an index of refraction thatis significant different than the refractive index of the opticalmaterial being coated. Fluorocarbon-containing coatings are particularlyadvantageous. Fluorocarbon coatings may be formed through plasmapolymerization of fluorine-containing monomers such astetrafluoroethylene, hexafluorobenzene, or hexafluoropropene. Chemicalcladding is not necessarily required. In some applications, so-called“air-cladding” may suffice, in that the index of refraction of airdiffers sufficiently from that of a polymeric material serving asoptical wave guide. Air-cladding is generally suitable when the surfaceof the optical wafer (other than the analyte-reactive sensor zone) isnot likely to be in contact with water or water-based fluid and remainsdry. While the cladding operation (block 53) is therefore optional, itmay be quite advantageous in many applications.

The optical wafers themselves may be formed from any of many suitableoptically transparent compositions. Suitable choices include polymericcompounds such as celluloids, cellulose acetates, polyesters,polystyrenes, polymethacrylates, polyolefins, halogen-containingpolyolefins, polysulfones, polycarbonates, and copolymers or terpolymersof these different compositions. Other suitable choices includecellulose acetates, polycarbonates, methyl methacrylate polymer andcopolymers, polystyrene, and styrene-acrylonitrile copolymer. Continuoussheeting of many of these compositions is available and amenable tobeing processed through die-cut roller machines. Alternatively, sheetsmay be handled and processed by means of various types of cutting andembossing equipment. Processing may be done at room temperature or atelevated temperatures. For sheeting where rigidity of the polymercomposition may present processing difficulty, elevated temperaturessufficient to soften the polymer composition may be employed.

Following the embossing or die-cutting operations, partial separation ofthe sheeting along the longitudinal lines 11 may be performed to exposethe tips of the optical wafers 14 for the subsequent texturingoperations. The optical wafers 14 may be left connected at their basesfor the subsequent texturing operation, or separated at their basesalong with their tips. FIG. 2 illustrates the latter option, where theoptical wafers 22 are separated at their tips and bases. The resultingseries of exposed tips and exposed apertures resulting from separationand discard of the cutouts 24 outlined by oval cutout lines 23 are readyfor the texturing operation. This separation operation is shown as block54 in FIG. 5.

If the narrow strips are not already rolled up, they may be formed intoa roll as shown in block 55 of FIG. 5. Alternatively, they may bestacked. FIG. 3 illustrates a roll 31 or coil of optical wafers 32.These optical wafers 32 are still joined side-to-side at the transverselines 33, which are shown as being formed on both sides of the stripsbut which may be formed on only one side if desired. However, theoptical wafers 32 now have projecting tips 34, which are narrowed incomparison to the width of the rectangular portion of the opticalwafers, wherein the top surface of each of the tips is bare, i.e.exposed, as opposed to being clad. Coating with a cladding beforeperforming a cutting and separation at longitudinal lines 11 (FIG. 1)results in tips 34 having an unclad area corresponding to the separationat the longitudinal lines 11. Thus the very top surface of the tip isessentially bare polymer, readily accessible for any subsequent surfacetexturing process. Any desired number of wafers may be in these rolls,depending upon the ease or difficulty of handling small or largediameter rolls of the wafers. Excising of these rolls from the cladsheeting may be accomplished by passing the clad sheeting through a diecutting roller assembly, but may also be done by passing through amounted array of razor blades or through an array of shearing rollers.Registration of the lines so as to achieve proper placement of theseparations may be done using techniques well known to persons ofordinary skill in the art. Alternatively or in concert, the cutoutapertures may be used for locating or registering the sheeting relativeto cutting blades. In particular, accurate placement of the longitudinallines 11 (FIG. 1) is particularly desired, so that all exposed tips willbe of the same cross-sectional area throughout a roll of the wafers.

The roll 31 is then passed through a texturing operation wherein thetips are subjected to a texturing treatment to provide a greatlyincreased surface area for deposit of an analyte-reactive reagent, sothat a sufficiently strong signal may be generated in a chromaticanalysis method for rapid and accurate assay. Texturing may be performedusing various techniques. One suitable technique involves texturing bymeans of a directed beam of atomic oxygen, as set forth in U.S. Pat. No.5,560,781 issued Oct. 1, 1996 to Banks et al., which is incorporatedherein in its entirety by reference thereto. Atomic oxygen may be usedto microscopically alter the surface morphology of polymeric or plasticmaterials in space or in ground laboratory facilities. For polymeric orplastic materials whose sole oxidation products are volatile species,directed atomic oxygen reactions produce surfaces of microscopic cones.However, isotropic atomic oxygen exposure results in polymer surfacescovered with lower aspect ratio sharp-edged craters. Isotropic atomicoxygen plasma exposure of polymers typically causes a significantdecrease in water contact angle as well as altered coefficient of staticfriction. Atomic oxygen texturing of polymers is further disclosed andthe results of atomic oxygen plasma exposure of thirty-three (33)different polymers, including typical morphology changes, effects onwater contact angle, and coefficient of static friction, are presentedin an article by Banks et al., “Atomic Oxygen Textured Polymers,” NASATechnical Memorandum 106769, Prepared for the 1995 Spring Meeting of theMaterials Research Society, San Francisco, Calif., Apr. 17-21, 1995,which hereby is incorporated herein in its entirety by referencethereto. In this regard, organopolymeric plastics amenable to oxidationand etching by atomic oxygen are advantageous for use in the preparationof sensors based on the optical wafers described herein, such plasticsalso needing to display good transparency characteristics toward lightfrequencies intended to be used in subsequent sensors. Some examples ofsuch plastics include poly(methyl methacrylate), polystyrene,styrene-acrylonitrile copolymer, various methyl methacrylate copolymers,and polycarbonate.

FIG. 4 illustrates a single optical wafer prepared in accordance withthe methods described here. Most of the optical wafer 41 is a generallyrectangular-shaped portion 42 which tapers into a narrowed tip 43 havinga distal surface 44 whereupon a textured surface may be formed andwherein a deposit of an analyte-reactive reagent may be made.

These optical wafers may have thicknesses in the range of 1 micrometer(μm) to 10,000 μm, preferably in the range of 10 μm to 1000 μm, and morepreferably in the range of 200 μm to 700 μm. Polymeric films or sheetinghaving thicknesses in the range of 276 μm to 552 μm are particularlypreferred. The length of the optical wafer is conveniently on or about250 mm, but may be shorter or longer, such as in the range of 50 mm to1000 mm. In a device for blood glucose determination incorporating botha lancet and the optical wafer, the lancet customarily has a length ofapproximately 250 mm itself, and an optical wafer of the sameapproximate length is advantageous for handling, packaging and usagecharacteristics. The width of the tip at its exposed end may range from0.1 mm to 10 mm, preferably 0.5 mm to 5 mm, more preferably 1 mm to 2mm. The narrowest widths may involve additional effort to accurately cutand control, while the widest widths may present an unnecessarily largesurfaces to wet out with a blood drop in the range of 0.1 μl to 0.5 μl(microliter). For particular ease in handling, the shape of the opticalwafer may be generally rectangular on three sides, the fourth side beinga tapered tip. The width of the body of the wafer is illustratively 2-to 100-fold the width of the tip, preferably 2.5- to 5-fold the width ofthe tip. A particularly preferred wafer formed in accord with thisinvention would have a length of approximately 250 mm, a width ofapproximately 4.5 mm along most of its length dimension, and a taperingto a tip, the width of the tip being approximately 1.6 mm.

FIG. 6 shows various illustrative clusters of optical wafers formed fromdifferent cutout configurations. Cluster 62 uses oval cutouts, cluster63 uses circular cutouts, cluster 64 uses diamond cutouts, cluster 65uses elongated diamond cutouts, and cluster 66 uses a star-like cutout.The tips of the optical wafers need not be centered and the the opticalwafers need not be symmetrical, as shown in cluster 67 which uses atriangular cutout. Other cutout configurations are contemplated as well,with the choice of a particular cutout configuration being a matter ofdesign choice both for manufacturing considerations and opticalperformance. For practical purposes of handling, the length of the sidesof the wafers in the main portion is preferred to exceed the projectinglength of the tip of the wafer, but as shown by cluster 65, this is nota requirement.

The rolls 31 are further processed in an analyte-reactive reagentdeposition operation 57 (FIG. 5), which may include the deposition ofhollow microspheres for enhanced sensitivity, in accordance with theaforementioned Nomura patent documents. An analyte-reactive reagent forthe analyte is disposed on the tips 34 of the optical wafers 32 inoptical communication therewith, and a plurality of light scatteringparticulate bodies may be dispersed through the analyte-reactivereagent, the particulate bodies being adapted to contribute toreflectance of light from the optical material body back into theoptical material body through at least a portion of the analyte-reactivereagent, when the analyte-reactive reagent is in reaction with theanalyte. In particular, use is made of hollow polymeric microspheres,which provide for significantly augmented reflectance of a light beamemitted from the optical material into the sampling zone. Furtherdescribed is a device wherein exists a sampling zone associated with ananalyte-reactive reagent wherein a portion of the reagent is disposedbetween the surface of the optical material and the hollow polymericmicrospheres, the hollow polymeric microspheres providing forreflectance of a light beam emitted from the optical material into thesampling zone.

A specific and particularly advantageous implementation may besummarized as follows. A continuous roll of optically transparentsheeting, preferably based on a polymethacrylate-based polymer orcopolymer, is passed through a machine roller operation wherein cutoutsare excised and transverse lines are embossed into the roll of sheeting.The roll is then passed through a gas plasma apparatus wherein afluorocarbon based coating is applied to all exposed surfaces of thesheeting to create optical cladding. The roll of clad material is thenpassed through a cutting operation wherein the sheeting is slit alonglongitudinal lines into continuous strips. These strip rolls are thenplaced, in roll form, in a chamber and the exposed tips are etched bymeans of a directed beam of atomic oxygen. The textured tips of thestrip rolls are then impregnated with a fluid slurry mixture ofanalyte-reactive reagent and polymeric hollow microspheres (such asavailable as Ropaque®, a tradename of Rohm and Haas) and dried, thefluid mixture depositing the reagent and the microspheres in thecrevices in the etched tips. The strip rolls are then separated intoindividual sensor strips and loaded into small cartridges customarily ofa type used in blood glucose testing by diabetic patients.

The specific implementation is now described in greater detail, withreference to the figures where appropriate. With reference to FIG. 1, asuitable sheet of an optically transparent plastic is passed through afirst step wherein oval, diamond, or other approximately similarlyshaped die-cut lines 13 are formed, wherein also transverse lines 12 areembossed to a depth that will allow later separation or detachment ofone wafer from another in a later step. Machine-direction die-cut lines10, 11 are not done at this stage, but are done in a later step. Thecutouts are then removed from the continuous sheet, providingessentially a perforated sheet of material. Multiple arrays ofperforations are preferably positioned in the continuous sheet ofmaterial in parallel arrangements, thus providing a parallel array of“double” wafers held side to side by narrowed connecting bridges of thesheet material and flat base to flat base where the longitudinal lines10 and 11 are not not yet effected. The perforated/ cut/ embossed sheetis then passed through a coating step wherein the surface is coated witha cladding of an organopolymeric material, preferably of high fluorinecontent. Cladding polymer may be applied by dip-coating, spraying,extrusion coating, or gas plasma coating. Applying such a coating by gasplasma polymerization is particularly suited to this intendedapplication. The resulting continuous clad sheet is then passed througha die-cutting operation to produce strips of clad wafers, wherein tipsand bases are separated from previously adjoining tips and bases onadjacent strip rolls. The tips are narrow, and their distal surfaces donot having cladding because of the exposure at the longitudinal line 11having now been performed. The strips, which can be easily handled inroll form, are then exposed to atomic oxygen texturing applied to theexposed tip surfaces. Because of the presence of cladding materialelsewhere on the sheet surfaces, including the embossed lines and thesurfaces exposed earlier in the cutout step, atomic oxygen texturing isin practice naturally restricted primarily to the freshly exposed sheetmaterial on the tip distal surfaces. Subsequent to the atomic oxygentexturing (or to other means of texturing of the exposed tip surfacesthat may become applicable), the textured tip strips are treated so asto deposit an analyte-reactive reagent, preferably withreflectance-enhancing hollow polymeric beads, as disclosed in theaforementioned Nomura patent documents. The resulting optical wafer issuitable for use as an optical sensor element capable of assayinganalytes such as blood glucose when contacted with a biological fluid atthe tip and illumined with a light beam into the end of the waferopposite to the tip.

A sample of blood or other body fluid is presented to a surface of thetip of the optical wafer, wherein an analyte-reactive reagent is presentas a coating. The surface may be smooth, or the surface may beadvantageously textured so that it presents the morphology of a field ofelongated projections. The projections may be suitably spaced apart toexclude certain cellular components such as blood cells in a body fluidsample from entering into the spaces between the projections, whilepermitting the remaining part of the body fluid sample, which containsthe analyte, to enter into those spaces.

The targeted analyte contacts an analyte-specific chemistry on thesurface of the sensor, whereupon the analyte and a specific reagentinteract in a manner that is optically detectable. Suitableanalyte-specific chemistries may include receptor molecules as well asreactive molecules. Commonly, analyte-specific chemistries includecomponents that generate colored species, and optical detection is basedon the density and spectral nature of the colored species. In the caseof blood containing cellular elements such as erythrocytes, spatialexclusion of the erythrocytes from the zone of the reagent is animportant advantage of suitably textured analytical sites, when certaincolor development chemistries are used where the erythrocytes wouldinterfere in such color-based assays. In commonly applied chemistriesfor analyzing blood sugar levels, for instance, erythrocytes oftenabsorb light in the same general range of light frequencies in opticaldeterminations, and must be excluded in some manner so as not tonegatively influence the analytical results. The nature and arrangementof the analyte-specific chemistry varies depending on the application.For example, the analyte-specific chemistry may be a layer of one typeof chemistry or an ordered array or a finely mixed composite ofdifferent types of analyte-specific chemistries. For convenience, thesevarious options are grouped together during the remainder of thisdisclosure by using the term “analyte-reactive reagent”. The opticallydetectable change may occur specifically in the coating of theanalyte-reactive reagent, or in a deposit developed on the coating (suchas by binding of targeted analytes), or by development of reactionproducts in the fluid immediately in contact with the reagent. Forpurposes of this disclosure, these various possibilities which eachinvolve slightly different spatial regions are included under the term“reagent sampling zone”.

A light beam of a suitable frequency or range of frequency istransmitted through the base of the optical wafer at the opposite endthereof and from there through the tip into the reagent sampling zone.Changes in the spectral nature of the light beam advantageously occur asa function of optically detectable changes in the reagent sampling zonedue to interaction of the analyte-reactive reagent with an analyte inthe fluid to be analyzed. When detecting the spectral changes usingreflectance spectroscopy, any part of this light beam that radiates in adirection away from the optical material through which the light beam isbrought to the reagent sampling zone does not generally reenter theoptical material, and does not contribute to the measurement. Thetechniques described herein enhance the amount of this light beam thatis returned to and captured within the optical material for subsequentanalysis. This technique for enhanced reflectance is optimally in theform of particles that scatter light. These particles may be composed ofinorganic or organic materials. Inorganic particles useful asreflectance enhancing agents include silicates and related glasses, andmay be in the shape of beads or similarly spherical shapes. They may besolid or hollow. Organic particles useful as reflectance enhancingagents include natural and synthetic polymers of various compositions,and may also be solid or hollow. Hollow beads are particularlyeffective. So that the analyte-reactive reagent may be accessed by thefluid sample, these reflectance enhancing particles are desirably notfilm-forming, meaning that a coating or array of these particles doesnot form a film impenetrable to fluid transport. These particles areassociated with an analyte-reactive reagent coating, preferably byco-deposition as a mixed coating on the surface of an optical material,so as to be present in the reagent sampling zone. In practice, theanalyte-reactive reagent is present as a coating intimately in contactwith a surface of the optical material, and the suitable reflectanceenhancing particles are in contact with the reagent layer but optimallyextend beyond the reagent layer spatially. Thus, in one configuration, amajority of the analyte-reactive reagent is advantageously sandwichedbetween the optical material and the reflectance enhancing particles. Aparticularly effective arrangement is a textured surface on an opticmaterial wherein both the analyte-reactive reagent and the reflectanceenhancing particles are deposited within valleys or crevices of thesurface.

The reflectance enhancing particles are normally to be applied to thesurface of an optical material from an aqueous dispersion. The particlesmay be co-deposited on the surface along with the analyte-reactivereagent in a single step. Alternatively, the particles may be depositedin a separate step, preferably after first depositing a coating of thereagent. Drying of the coating or coatings at some point in the processis accomplished so as to present a dry sensor for handling and storage.

Various chemistries may be employed as analyte-reactive reagents, and avariety of analytes in blood or other biological fluids may be assayedby use of the sensors made accordingly with the invention disclosedherein. For blood glucose, which is a commonly assayed analyte, asuitable reagent is described in the aforementioned Nomura U.S. Pat. No.8,008,068 and is useful as well in the sensor described herein.

The description of the invention including its applications andadvantages as set forth herein is illustrative and is not intended tolimit the scope of the invention, which is set forth in the claims.Variations and modifications of the embodiments disclosed herein arepossible, and practical alternatives to and equivalents of the variouselements of the embodiments would be understood to those of ordinaryskill in the art upon study of this patent document. Moreover, anyspecific values given herein are illustrative, and may be varied asdesired. These and other variations and modifications of the embodimentsdisclosed herein, including of the alternatives and equivalents of thevarious elements of the embodiments, may be made without departing fromthe scope and spirit of the invention, including the invention as setforth in the following claims.

1. An optical sensor element for determination of an analyte in abiological fluid, comprising: a flat optical waveguide elongated in alongitudinal direction and having two parallel major surfaces and anedge contiguous to the major surfaces, a portion of the edge being a tiptransverse to the longitudinal direction, a further portion of the edgebeing a base transverse to the longitudinal direction, and furtherportions of the edge being two sides extending between the base and thetip generally in the longitudinal direction; the tip being textured; themajor surfaces being coated with cladding; and each of the sides beingpartially coated with cladding toward the base and being fully coatedwith cladding toward the tip; further comprising an analyte-reactivereagent disposed on the tip.
 2. The optical sensor element of claim 1wherein the optical waveguide comprises an optically transparent polymerbody.
 3. The optical sensor element of claim 2 wherein the majorsurfaces, the tip, and the sides are surfaces of the opticallytransparent polymer body, and the cladding comprises a fluorocarboncomposition.
 4. The optical sensor element of claim 1 further comprisinga plurality of particulate bodies dispersed through the analyte-reactivereagent, the particulate bodies being adapted to contribute toreflectance of light from the optical waveguide back into the opticalwaveguide through at least a portion of the analyte-reactive reagent,when the analyte-reactive reagent is in reaction with the analyte. 5.The optical sensor element of claim 1 wherein the tip presents atextured field of elongated projections.
 6. An optical wafer for use inmanufacturing an optical sensor element, comprising: a flat opticallytransparent body elongated in a longitudinal direction and tapering downat one end to a tip, the tip being transverse to the longitudinaldirection and presenting a textured field of elongated projections; andan analyte-reactive reagent disposed on the tip.
 7. The optical wafer ofclaim 6 further comprising a plurality of particulate bodies dispersedthrough the analyte-reactive reagent, the particulate bodies beingadapted to contribute to reflectance of light.
 8. The optical wafer ofclaim 7 wherein the particulate bodies comprise hollow polymeric spherestransparent to visible light.
 9. The optical wafer of claim 6 whereinthe optically transparent body is generally rectangular in shape. 10.The optical wafer of claim 6 wherein: the flat optically transparentbody has two parallel major surfaces and an edge contiguous to the majorsurfaces, the tip being a portion of the edge, a further portion of theedge being a base transverse to the longitudinal direction; and furtherportions of the edge being two sides respectively extending between thebase and the tip generally in the longitudinal direction; the majorsurfaces being coated with cladding; and each of the sides beingpartially coated with cladding toward the base and being fully coatedwith cladding toward the tip.
 11. The optical wafer of claim 10 whereineach of the sides toward the base comprises a ridge of unclad opticallytransparent body material, flanked by respective coterminous lengths ofcladded optically transparent body material.
 12. A method of fabricatingoptical wafers for biological fluid sensors, comprising: establishing aplurality of cutouts in a sheet of optically transparent polymermaterial to define respective tapered portions of the optical wafers andexpose edges thereof; establishing a plurality of transverse lines inthe sheet to define respective main portions of the optical wafers andpartially expose edges thereof; separating the sheet along a pluralityof longitudinal lines into a plurality of strips to expose respectivetips of the optical wafers; applying a texturing treatment to the tipsexposed in the separating step to form a field of elongated projectionsin the tips; depositing a fluid slurry mixture of analyte-reactivereagent and light scattering particles within the field of elongatedprojections; and following the texturing treatment applying step and thefluid slurry mixture depositing step, separating the optical wafers fromone another along the transverse lines.
 13. The method of claim 12further comprising: applying a cladding of a fluorocarbon composition tothe sheet following the cutouts establishing step and the transverselines establishing steps and prior to the separating step, including theexposed edges of the tapered portions of the optical wafers and thepartially exposed edges of the main portions of the optical wafers. 14.The method of claim 12 wherein the cutout establishing step comprisesurging a plurality of punches having shaped cutting edges against thesheet to define and remove the cutouts from the sheet.
 15. The method ofclaim 12 wherein the cutout establishing step comprises: establishing aplurality of cutout lines to define the cutouts; and punching out thecutouts from the sheet.
 16. The method of claim 15 wherein the cutoutlines establishing step and the transverse lines establishing step areperformed contemporaneously.
 17. The method of claim 12 wherein thetransverse lines are embossed lines.
 18. The method of claim 12 whereinthe transverse lines are cut lines.
 19. The method of claim 12 furthercomprising rolling the strips into one or more rolls prior to thetexturing treatment applying step and the fluid slurry mixture depositstep, wherein the texturing treatment applying step and the fluid slurrymixture deposit step are performed on the tips as disposed in the one ormore rolls.
 20. The method of claim 12 further comprising stacking thestrips into a stack prior to the texturing treatment applying step andthe fluid slurry mixture deposit step, wherein the texturing treatmentapplying step and the fluid slurry mixture deposit step are performed onthe tips as disposed in the stack.
 21. The method of claim 12 wherein:the texturing treatment applying step comprises applying a directed beamof atomic oxygen to the tips; and the light scattering particlescomprise hollow polymeric microspheres.